Posted on
Tuesday 1 October 2013

The first half of medical school was hard for me. Unlike college, the material itself wasn’t that difficult, but there was just so much of it. And after college, two more years of lecture halls, labs, and endless facts was a lot, no matter how fascinating. I had nothing to hang the deluge of unfamiliar material on and I wondered how I would remember any of it. At that point in training, you don’t yet know that you’ll go over it again and again, and later, when you see it in a case, all that stuff will come together in a useful way. I remember one very sleepy afternoon when a biochemistry professor was droning on about vitamins. He started talking about Scurvy – a Vitamin C deficiency seen in British sailors in antiquity. He said something like "a classic finding is bleeding into the hair follicles with corkscrew hairs." He went on to tell us they figured out they could cure it with lemons and limes, so they put the juice in the rum rations to make sure it got taken. It’s why British people are called "limeys." I recall thinking in that lecture, "corkscrew hairs? fat chance on remembering that!"

Some five or so years later, I was a medical resident and was called to see a patient in the ER. He was a deaf mute who lived in a flop house of some sort – a forgotten person. He was covered with bruises, anemic, and looked malnourished. He had a rash, and there they were, "corkscrew hairs with bleeding at the base." I blurted out, "This man has Scurvy!" I think the Interns thought I was blowing smoke, but that sleepy biochem lecture I was sure I would forget came back with more clarity than the day I heard it long before. It was the only case of Scurvy I ever saw [or for that matter, any of us ever saw]. We confirmed it with Vitamin C levels, and watched with amazement as his symptoms melted in a matter of days on a regular diet with a full glass of Orange Juice with every meal. His corkscrew hairs were photographed by every dermatologist on the campus and he is probably immortalized in textbook pictures to this day. Wouldn’t it be nice if medicine were all like that? An objective finding [corkscrew hairs with bleeding into the follicle] makes the diagnosis [Scurvy] cured by a few balanced meals [Vitamin C]?

In the annals of the disease, two men are mostly credited with discovering a cure: James Lind and Gilbert Blane. While citrus fruits had long been anecdotally treated as a cure, so were a whole host of other naturopathic remedies, and it fell to the young surgeon’s mate James Lind to design a now-famous test of various remedies. Lind, who enlisted at the age of twenty-three without much formal medical training, became obsessed with scurvy and its effects, and in 1747 gathered together twelve sailors with scurvy, which he ordered fed the same meals for breakfast, lunch and dinner, and then divided them into six groups, administering various known cures for scurvy to each group:

One quart of hard cider

Twenty-five drops of elixir vitriol

Two spoonfuls of vinegar

Half a pint of sea water

Two oranges and one lemon

A medicinal paste made up of garlic, mustard see, balsam of Peru, dried radish root and gum myrrh; along with a drink of barley-water with tamarind, and finally crème of tartar as a laxative

It took only six days for those on citrus fruits to recover, though the hard cider group also saw some limited improvements in symptoms. Those who gargled the elixir vitriol had cleaner mouths and gums, but otherwise had not improved much. Lind saw no improvement in the sea water, vinegar, or medicinal-paste-and-tamarind-water groups. He concluded: “oranges and lemons were the most effectual remedies for this distemper at sea.”

Despite this undeniable conclusion, Lind’s advice didn’t immediately take hold, and scurvy rates continued to rise in the Navy. In 1780, three-thousand cases of scurvy were reported in six months in the West Indies fleet, and Admiral George Brydges Rodney appointed his friend, Gilbert Blane, Physician to the Fleet, hoping for some kind of answer. Within a few months Blane came to the same conclusions as Lind had decades earlier: “scurvy, one of the principal diseases by which seamen are afflicted, may be infallibly prevented, or cured, by vegetables and fruits, particularly organs, lemons, or limes.” The intransigence of bureaucracy kept Blane’s recommendations from being widely implemented for another fifteen years, until in 1795 he was appointed to the Board of Sick and Wounded Sailors. Soon after, lemon juice was added as a staple to English ships, and incidences of scurvy plummeted. The British Navy had finally seen the light, and from 1796 until 1814, according to Carpenter, the British Navy distributed over 1.6 million gallons of lemon juice.

It was the earliest of clinical trials – unblinded, open label, a questionable Placebo [sea water], powered only to detect a "cure." They say it was intransigent bureaucracy that held up implementation of Lind’s findings, but I wonder if even then it wasn’t money – the cost of the lime juice. Lind, himself, is immortalized in the James Lind Library, the James Lind Initiative, the James Lind Alliance, and ultimately the Cochrane Collaboration, all associated the work of Sir Iain Chalmers. The Cochrane Collaboration is an independent group of volunteer scientists who "study the studies" – producing meta-analyses considered widely to be as close to the truth as we are likely to get.

As wonderful as the Cochrane and other meta-analyses are, they can’t solve the current dilemma of confusing and corrupted clinical research. First, they only study studies, and in many cases, all the studies for a particular drug were financed by the manufacturer. There, they can question methodology, but have no independent benchmark. They also deal with the epidemic problem of unpublished studies – for example the Tamiflu problem where the data is withheld by the manufacturer. Finally, meta-analyses are, by definition, latecomers – arriving after the drug has been marketed and is already in use.

Solutions to date have been largely ineffective – for example, clinicaltrials.gov. Published papers often deviate from the descriptions on clinicaltrials.gov. The requirement to report results at the end of the trial is uniformly ignored. And many trials are never registered. In addition, many journals have no requirement for registration or reported results prior to publication. It’s not that the idea of clinicaltrials.gov is inadequate, it’s simply that it has been ignored – even by the FDA who approve drugs that have not been fully reported. And so, the current effort, AllTrials, is an attempt to circumvent the problem of previous efforts by requiring data transparency up front for all clinical trials, an effort being resisted with the usual vengeance by the pharmaceutical industry. They speak of Trade Wars with China, of "CCI" [Commercially Confidential Information], of patient confidentiality, all without addressing the whole point that they’re fighting to keep me, the doctor, and you, the patient, from knowing the actual results of the study, without addressing their criminal track record as an industry.

Ben Goldacre called the process that results in the obfuscation of actual clinical trial results tediousness in his Ted Talk. That’s not bad, but as I looked at the article above about Lind’s first clinical trial, I also liked the term bureaucratic intransigence, because that’s what it comes down to. What I thought of was the idea of patient confidentiality. Clinical trial subjects aren’t really patients. Why not add a release for anonymized data to the consent form? I can’t imagine they’d care. Lind’s sailors would surely likely like other Scurvy afflicted sailors to know what Lind found out, if only to protect them from toxic gargles. But beyond that, why even leave the control of the raw data in the hands of the pharmaceutical companies in the first place? Dr. Fiona Godlee says [goldacre and godlee…]:

"Unless we can find a solution to the commercial incompetence problem, we have to recognize that the pharmaceutical industry has an irreducible conflict of interest in relation to the way it represents its drugs, in science and in marketing. And unless we can resolve this in a way that is more in the public interest and in patients’ interest, I would argue that drug companies should not be allowed to evaluate their own products."

They already don’t "evaluate their own products". They contract independent clinical research organizations. Why not insist that these organizations file verbatim their reports to the drug companies with the FDA prior to breaking the blind? make it a requirement of licensure? make any needed confidentiality a responsibility of the CRO? Confidentiality should mean confidentiality from the pharmaceutical company too!

For that matter, why should the FDA collude with this craziness? Why not make all data filed with the FDA by CROs or companies seeking approval public? What’s the point of the FDA keeping secrets for anyone. If the company has Commercially Confidential Information, there’s no reason for either the CRO or FDA to know about it anyway. The pharmaceutical companies want to retain their control at both junctures. Why not follow Dr. Godlee’s advice by removing them from the loop altogether? If they want to apply for approval, the FDA would already have the raw data, as would we. All the bureaucratic intransigence the industry is fighting to hold on to is only a strategy to keep the truth hidden. So negotiating with them is a waste of time, as it has always been.

Medicine has come a long way since the 18th century and the days of James Lind. Bureaurocratic intransigence, on the other hand, hasn’t moved an inch. It took fifty years for Lind’s discovery to translate into policy and actual treatment. By any measure, we ought to be way ahead of that right now, but we’re not. We don’t really find out about either efficacy or adverse events until after the fact, actually after the patent life runs out. We can [and should] do a lot better than that…